scholarly journals T cells expanded from renal cell carcinoma are tumor-reactive but fail to produce IFN-γ, TNF-α or IL-2

2020 ◽  
Author(s):  
Saskia D. van Asten ◽  
Rosa de Groot ◽  
Marleen M. van Loenen ◽  
Jeroen de Jong ◽  
Kim Monkhorst ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kidney Tissue ◽  
Effector Memory ◽  
Autologous Tumor ◽  
Tnf Α ◽  
Ifn Γ

AbstractMetastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions.We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. T cell infiltrates were increased in the tumor lesions, and CD8+ T cell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with a high percentage of infiltrated T cells compared to autologous kidney, and coincided with increased ex vivo CD25 expression on CD8+ T cells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-γ, TNF-α or IL-2, they failed to do so in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive T cells. Their lack of tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.

scholarly journals Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma

2021 ◽  
Vol 9 (2) ◽  
pp. e001823
Author(s):  
Siyuan Dai ◽  
Han Zeng ◽  
Zhaopei Liu ◽  
Kaifeng Jin ◽  
Wenbin Jiang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Immune Function ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Tnf Α ◽  
Ifn Γ

BackgroundChemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFH have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8+T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13+CD8+T cells in clear cell renal cell carcinoma (ccRCC).MethodsWe analyzed prognostic value and immune contexture that associated with CXCL13+CD8+T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13+CD8+T cells and total CD8+T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC.ResultsIntratumoral CXCL13+CD8+T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13+CD8+T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8+T cells in high-level CXCL13+CD8+T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13+CD8+T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3+ regulatory T cells, TLS and decreased natural killer cells, GZMB+ cells.ConclusionsIntratumoral CXCL13+CD8+T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13+CD8+T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13+CD8+T cells abundance impaired total CD8+T cells’ immune function. Intratumoral CXCL13+CD8+T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13+CD8+T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.

scholarly journals Renal Cell Carcinoma-Infiltrating CD3low Vγ9Vδ1 T Cells Represent Potentially Novel Anti-Tumor Immune Players

2021 ◽  
Vol 43 (1) ◽  
pp. 226-239
Author(s):  
Hye Won Lee ◽  
Chanho Park ◽  
Je-Gun Joung ◽  
Minyong Kang ◽  
Yun Shin Chung ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Γδ T Cells ◽  
Gene Set Enrichment Analysis ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Γδ T Cell

Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery.

scholarly journals T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production

2021 ◽  
Vol 10 (1) ◽  
pp. 1860482
Author(s):  
Saskia D. van Asten ◽  
Rosa de Groot ◽  
Marleen M. van Loenen ◽  
Suzanne M. Castenmiller ◽  
Jeroen de Jong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tnf Α ◽  
Ifn Γ

Metabolic barriers to immunotherapy in renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11560-11560
Author(s):  
Katy Beckermann ◽  
Peter Siska ◽  
Frank Mason ◽  
Kimryn Rathmell ◽  
Jeffrey C Rathmell
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mitochondrial Morphology ◽  
Dependent Manner ◽  
Syngeneic Mouse Model ◽  
Healthy Control

11560 Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment as a result of cancer metabolism. A majority of patients treated with immune checkpoint inhibitors recently approved by the FDA fail to exhibit a clinical response. The extent to which metabolic conditions within the tumor impede T cell activation and anti-tumor effector function in renal cell carcinoma (RCC) are unknown. Methods: Under the IACUC protocol M1600005-00, BALB/c or Rag mice were subcutaneously injected with 100,000 Renca cells obtained from ATCC and growth monitored by caliper measurements in 3 dimensions every 3 days. In vivoPD-1 blockade was performed by 200 mcg/i.p. injection every 3 days using purified mPD-1 (BioXcell, J43). Deidentified tissue donations from patients with RCC were collected under the IRB protocol #151549 and processed into single cell suspensions following mechanical dissociation for the functional assays indicated below. Results: Through work with Rag deficient mice lacking functional B and T cells, we have established that tumor growth is regulated in a T cell dependent manner as evidenced by earlier formation and faster tumor growth. In a syngeneic mouse model of RCC (RenCa), we find that inhibition of PD-1 delays tumor growth and size. Tumor infiltrating lymphocytes (TILs) were abundant in patient-derived RCC, but are phenotypically distinct and are impaired both functionally and metabolically from healthy control. Instead of efficient use of aerobic glycolysis, TILs fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 effector cells found in tumors have notable differences in mitochondrial morphology compared to healthy control CD8 T cells by electron microscopy and immunofluorescence where CD8 TIL are punctate and dispersed throughout the cell while healthy control CD8 mitochondria are fused in networks. Thus bypassing metabolic defects may partially restore TIL activation. Conclusions: Preclinical data suggests that improved understanding of metabolic dysfunction in TILs of RCC may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.

scholarly journals JAK3/STAT5/6 Pathway Alterations Are Associated with Immune Deviation inCD8+T Cells in Renal Cell Carcinoma Patients

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Elisabetta Cavalcanti ◽  
Margherita Gigante ◽  
Vito Mancini ◽  
Michele Battaglia ◽  
Pasquale Ditonno ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cell Cycle Regulation ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Cycle Regulation

To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneicCD8+T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responderCD8+T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution ofCD8+T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specificCD8+effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC.

scholarly journals Elevated Levels of Select Gangliosides in T Cells from Renal Cell Carcinoma Patients Is Associated with T Cell Dysfunction

2009 ◽  
Vol 183 (8) ◽  
pp. 5050-5058 ◽  
Author(s):  
Soumika Biswas ◽  
Kaushik Biswas ◽  
Amy Richmond ◽  
Jennifer Ko ◽  
Sankar Ghosh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Up-regulation of the interferon γ (IFN-γ)-inducible chemokines IFN-inducible T-cell α chemoattractant and monokine induced by IFN-γ and of their receptor CXC receptor 3 in human renal cell carcinoma

Cancer ◽  
2005 ◽  
Vol 103 (2) ◽  
pp. 258-267 ◽  
Author(s):  
Takahito Suyama ◽  
Mitsuko Furuya ◽  
Mariko Nishiyama ◽  
Yoshitoshi Kasuya ◽  
Sadao Kimura ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Interferon Γ ◽  
Human Renal Cell Carcinoma ◽  
Ifn Γ

Quantitative changes within the peripheral blood CD8highCD57+ T-cell subpopulation of patients with advanced renal cell carcinoma

2014 ◽  
Vol 20 (4) ◽  
pp. 147-159
Author(s):  
Marius Strioga ◽  
Vita Pašukonienė ◽  
Neringa Dobrovolskienė ◽  
Tadas Petraitis ◽  
Nijolė Kazlauskaitė ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Peripheral Blood ◽  
Renal Cell ◽  
Cell Subset ◽  
Cell Subpopulation ◽  
T Cell Subset

Background. Antitumor immunotherapy strategies, such as cytokine- based or cell-based immunotherapies, are designed to activate immune response against cancer cells, but considering that malignancy may be associated with the expansion of immunosuppressive components of antitumor immunity, it is likely that in such cases activation of the immune system would further enhance activity of these components, leading to more severe suppression of antitumor immune response thus making more favourable conditions for tumor progression. Materials and methods. We studied the expression of biomarkers, representing immunosuppressive (FOXP3) and cytotoxic (perforin, IFN-γ) CD8highCD57+ T-cell subpopulation functions in the peripheral blood of 34 patients with advanced clear cell renal cell carcinoma (RCC) and 26 controls by multicolour flow cytometry. Results. CD8highCD57+ T cell subpopulation of all CD8+ T cells in RCC patients was significantly higher compared to age-matched healthy controls (p = 0.003). It was found that the mean percentage of suppressive CD8highCD57+FOXP3+ T-cell subset and cytotoxic CD8highCD57+Perforin+ T-cell subset in the CD8highCD57+ T-cell subpopulation was significantly increased in RCC patients compared to controls (p = 0.0004 and p = 0.008, respectively). There was no strong and biologically relevant negative correlation between the expression of FOXP3 and Perforin in the peripheral blood CD8highCD57+ T-cell subpopulation of RCC patients. Conclusions. Subsets of immunosuppressive FOXP3+ T cell and tumor-attacking (cytotoxic) Perforin+ T cells in the CD8highCD57+ T-cell subpopulation are significantly increased in RCC patients compared to controls. These quantitative rearrangements are independent and individual for each RCC patient.

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